The ergoline ring is a tetracycle having the following structure ##STR1##
Substituted ergolines are known to be D-2 dopamine agonists having the ability to inhibit the secretion of prolactin and to affect favorably the symptoms of Parkinson's Syndrome. For example, in I when R is n-propyl, R.sup.1 is methylthiomethyl, and R.sup.2 is H, the substituted ergoline (as the mesylate salt) has been given the generic name pergolide--see U.S. Pat. No. 4,166,182. Pergolide is on clinical trial for the treatment of Parkinsonism and for certain conditions in which there is an excess of circulating prolactin, i.e., galactorrhea and inappropriate lactation. Another such ergoline drug is .alpha.-bromoergocryptine, named generically as bromocriptine--see U.S. Pat. Nos. 3,752,814 and 3,752,888--I when R.sup.2 is Br, R is methyl and R.sup.1 is the ergocryptine side chain. While both ergolines are D-2 dopamine agonists, bromocriptine, and to a lesser extent pergolide, also have some alpha blocking activity.
Ergolines are also known in which the C-10 carbon is replaced by oxygen--structure Ia below ##STR2##
U.S. Pat. No. 4,238,486 discloses a group of such trans-dl-4,6,6a,8,9,10a-hexahydro-7H-indolo[3,4-g,h][1,4]benzoxazines, said to have antihypertensive and prolactin inhibiting properties and to be useful in treating Parkinsonism. The disclosed compounds have a benzene-ring substituent at C-3 in 15 out of 18 compounds (see Table 1) and the 5,5a double bond may be saturated. Preferred dose levels for treatment of hypertension in humans are 20-100 mg per day though daily dose levels as high as 3 g. are permitted.
U.S. Pat. No. 4,318,910 claims indolo[3,4-g,h][1,4]benzoxazines according to Ia in which R.sup.1 is H but the 5,5a double bond may be hydrogenated and there may be an N-4 substituent (alkyl or aralkyl). Hypotensive, antihypertensive and rat-turning behavior (indicative of utility in treating Parkinsonism) are disclosed at doses ranging from 0.02 to 1.0 mg/kg. Daily oral dose levels in the range 0.002-1.0 mg/kg (0.15 to 75 mg per average 75 kg human per day) are advocated. The claims of the above two patents actually overlap. Only octahydro derivatives, those in which the 5,5a double bond is saturated, are claimed.
An ergoline part-structure according to formula II ##STR3## wherein R is lower alkyl, has been synthesized--see Bach et al, J. Med. Chem., 23, 481 (1980), particularly structures 25 on page 483 and 34 and 35 on page 484. (See also U.S. Pat. No. 4,235,909). The compounds show activity in prolactin inhibition and rat-turning behavior tests, indicating that D-2 dopamine agonist activity is present. Related compounds in which the C-1 carbon is replaced by nitrogen to form a pyrazole ring are also disclosed by Bach et al (loc. cit.)--see compounds 38-40--in U.S. Pat. No. 4,198,415. These pyrazoloquinolines are also D-2 dopamine agonists.
Octahydropyrazolo-[4,3-g][1,4]benzoxazines hexahydro-6H-thiazolo[4,5-g][1,4]benzoxazines and hexahydro-5H-pyrimido[4,5-g][1,4]benzoxazine have not hitherto been synthesized.